PROJECTSUMMARY/ABSTRACT Ourlong-termgoalistoidentifybioactivelipidmetabolitesthataredysregulatedinHIV-infectedindividualsand to gain a fundamental understanding of these lipid metabolites in liver disease pathogenesis and the developmentofliver-relatedcomplications.TheoverallobjectiveistoutilizeHIV/HCV-coinfectionasamodelto probeforunderlyingmechanismsofacceleratedliverfibrosisanddiseaseprogressionwiththeoverallpremise that there is a common final pathway of liver injury that is metabolic in nature. Our central hypothesis is that dysregulation of bioactive lipid metabolism reports on a common mechanism by which HIV-infection, antiretrovirals,andviralco-infectionsinteracttomodulatefibrogenesis.BasedonevidencethatHCVdramatically modulateshostcelllipidmetabolismandHIV-infectionandantiretroviralsalsoperturblipidpathways,wepropose that accelerated fibrogenesis in HIV is due, at least in part, to additive hits on lipid metabolism and excess accumulationofdetrimentallipidmetabolites,likeceramide.Thus,weusedamulti-targetedlipidomicsplatform to investigate bioactive lipids as predictors of liver fibrosis stage. Our preliminary studies indicate that (1) expressionofbioactivelipidscorrelateswithhistopathologicstageofliverdiseaseinpatientswithHIV/HCVand HCV infections, and (2) clearance of HCV using DAA regimens results in rapid changes in lipid homeostasis pathways.TheproposedworkwilltestourhypothesisthatdysregulationofbioactivelipidmetabolisminHIV- infectionplaysakeyroleinprogressiveliverdisease,aswellasthecorollaryhypothesisthatvariationsinlipid expression can be used as noninvasive assessments of liver disease complications. We will accomplish the objectiveoftheapplicationbypursuingthefollowingSpecificAims:(1)Discoverandvalidatespecificexpression patternsofcirculatingbioactivelipidmetabolitesthatarepredictiveofend-stageliverdiseasecomplicationsin patients with HIV/HCV-coinfection;? (2) Determine unique patterns of circulating bioactive lipid metabolite expression for patients with HIV-infection including those with and without HCV co-infection and non-virally mediatedmetabolicliverdisease(NAFLD/NASH);?(3)Identifyspecificbioactivelipidmetaboliteexpressionthat ismodifiedbyDAAtreatment-inducedHCVclearanceandstatininitiationinHIV/HCVco-infectedpatients.The impactofthisproposalwillbetofundamentallychangeourunderstandingofthemetabolicmechanismsofliver diseaseinpeoplelivingwithHIV.Wewilldevelopanovel,noninvasiveassessmentofend-stageliverdisease complicationsthatwillhaveimmediateclinicalutility.Wewillalsoapplythisvalidated,noninvasivemetabolite profile as a tool to dissect lipid dysregulation related to HCV infection and other etiologies of liver disease includingHIVpersistenceandlong-termantiretroviraltoxicitywhichcouldinformfuturemechanisticstudiesand identifypotentialtherapeutictargetsoffibrogenesis.